Identification of dithiolethiones with better chemopreventive properties than oltipraz
| Autor: | Denise L. MacMillan, Thomas W. Kensler, Thomas J. Curphey, B. D. Roebuck, Adam H. Libby, Yulia Y. Maxuitenko, H. Howard Joyner |
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| Rok vydání: | 1998 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty Aflatoxin B1 Thiophenes Reductase Pharmacology chemistry.chemical_compound Liver Neoplasms Experimental In vivo Internal medicine Oltipraz medicine Animals Anticarcinogenic Agents Enzyme inducer Anticarcinogen biology Thiones General Medicine Glutathione Rats Inbred F344 Rats Endocrinology Glutathione S-transferase Liver chemistry Enzyme Induction Pyrazines Toxicity biology.protein |
| Zdroj: | Carcinogenesis. 19:1609-1615 |
| ISSN: | 1460-2180 |
| DOI: | 10.1093/carcin/19.9.1609 |
| Popis: | Oltipraz and related dithiolethiones are an important class of chemopreventive agents. Studies were undertaken to identify cancer chemopreventive dithiolethiones more active than oltipraz. Largely based upon enzyme induction activities in vitro, 17 dithiolethiones, including oltipraz, were analyzed for their ability to induce hepatic phase II enzyme activities in vivo. Of these compounds, 15 produced greater induction of NAD(P)H:quinone reductase and 11 yielded greater induction of glutathione S-transferase than oltipraz. All 17 dithiolethiones were then tested for their ability to inhibit acute hepatotoxicity by aflatoxin B 1 (AFB 1 ), which previously has been shown to be an intermediate predictor of chemopreventive activity. Rats were pretreated with dithiolethiones (0.3 mmol/kg body wt, three times a week per os) and challenged with two acutely toxic doses of AFBI (0.5 mg/kg body wt, once daily for two successive days per os). Inhibition of hepatotoxicity was measured by changes in body weight gain during AFB 1 challenge, reduction in levels of hepatic enzymes in serum and diminution of bile duct cell proliferation. Nine dithiolethiones spanning a range of responses in this toxicity screen were further tested for their ability to prevent AFBI-induced tumorigenicity, as assessed by a reduction in hepatic burden of putative preneoplastic foci. Six dithiolethiones were found to be considerably more effective than oltipraz in preventing AFB 1 -induced tumorigenesis. In general, dithiolethiones that were very effective in inhibition of acute hepatotoxicity were also found to be effective in prevention of hepatic tumorigenesis. |
| Databáze: | OpenAIRE |
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